biostudies-literatureTsou PSNHLBI NIH HHS649-56https://www.ebi.ac.uk/biostudies/studies/S-EPMC2672869biostudies-literatureUnknown329(2)We hypothesize that nitroglycerin (NTG) causes direct oxidation of multiple cellular sulfhydryl (SH) proteins and that manipulation of SH redox status affects NTG tolerance. In LLC-PK1 cells, we found that nitrate tolerance, as indicated by cGMP accumulation toward NTG, was accompanied by increased protein [(35)S]cysteine incorporation, significant S-glutathionylation of multiple proteins, and decreased metabolic activity of several SH-sensitive enzymes, including creatine kinase, xanthine oxidoreductase, and glutaredoxin (GRX). Cells overexpressing GRX exhibited reduced cellular protein S-glutathionylation (PSSG) and absence of NTG tolerance, whereas those with silenced GRX showed increased extent of NTG-induced tolerance. Incubation of LLC-PK1 cells with oxidized glutathione led to severThe Journal of pharmacology and experimental therapeuticsRole of glutaredoxin-mediated protein S-glutathionylation in cellular nitroglycerin tolerance.PMC2672869HL081580Tsou PSFung HLPage NAAddanki VHaas JAfalseRole of glutaredoxin-mediated protein S-glutathionylation in cellular nitroglycerin tolerance.We hypothesize that nitroglycerin (NTG) causes direct oxidation of multiple cellular sulfhydryl (SH) proteins and that manipulation of SH redox status affects NTG tolerance. In LLC-PK1 cells, we found that nitrate tolerance, as indicated by cGMP accumulation toward NTG, was accompanied by increased protein [(35)S]cysteine incorporation, significant S-glutathionylation of multiple proteins, and decreased metabolic activity of several SH-sensitive enzymes, including creatine kinase, xanthine oxidoreductase, and glutaredoxin (GRX). Cells overexpressing GRX exhibited reduced cellular protein S-glutathionylation (PSSG) and absence of NTG tolerance, whereas those with silenced GRX showed increased extent of NTG-induced tolerance. Incubation of LLC-PK1 cells with oxidized glutathione led to sever2009-01-01T00:00:00Z2009 May2025-04-22T06:48:51.635Z2019-03-27T00:21:58ZS-EPMC26728691922366610.1124/jpet.108.149997